RING Finger Protein RNF207, a Novel Regulator of Cardiac Excitation
- Roder, K., Werdich, A.A., Li, W., Liu, M., Kim, T.Y., Organ-Darling, L.E., Moshal, K.S., Hwang, J.M., Lu, Y., Choi, B.R., MacRae, C.A., Koren, G.
- The Journal of biological chemistry 289(49): 33730-40 (Journal)
- Registered Authors
- MacRae, Calum A.
- HSP70, RNF207, action potential duration, conduction velocity, endoplasmic reticulum (ER), hERG, protein complex, single-nucleotide polymorphism (SNP), zebrafish
- MeSH Terms
- Action Potentials/genetics
- Amino Acid Sequence
- Animals, Newborn
- Atrioventricular Block/genetics*
- Atrioventricular Block/metabolism
- Atrioventricular Block/physiopathology
- Embryo, Nonmammalian
- Ether-A-Go-Go Potassium Channels/genetics*
- Ether-A-Go-Go Potassium Channels/metabolism
- Excitation Contraction Coupling
- Gene Expression Regulation
- Genetic Vectors
- HEK293 Cells
- HSP70 Heat-Shock Proteins/genetics*
- HSP70 Heat-Shock Proteins/metabolism
- Molecular Sequence Data
- Myocytes, Cardiac/metabolism*
- Myocytes, Cardiac/pathology
- Protein Structure, Tertiary
- Ubiquitin-Protein Ligases/genetics*
- Ubiquitin-Protein Ligases/metabolism
- 25281747 Full text @ J. Biol. Chem.
Roder, K., Werdich, A.A., Li, W., Liu, M., Kim, T.Y., Organ-Darling, L.E., Moshal, K.S., Hwang, J.M., Lu, Y., Choi, B.R., MacRae, C.A., Koren, G. (2014) RING Finger Protein RNF207, a Novel Regulator of Cardiac Excitation. The Journal of biological chemistry. 289(49):33730-40.
Two recent studies [Newton-Cheh et al., Nature Genetics 41, 399-406 (2009); Pfeufer et al., Nature Genetics 41, 407-414 (2009)] identified an association, with genome-wide significance, between a single nucleotide polymorphism within the gene encoding RING finger protein 207 (RNF207) and the QT interval. We sought to determine the role of RNF207 in cardiac electrophysiology. Morpholino knockdown of RNF207 in zebrafish embryos resulted in APD prolongation, occasionally a 2:1 atrioventricular block and slowing of conduction velocity. Conversely, neonatal rabbit cardiomyocytes infected with RNF207-expressing adenovirus exhibited shortened APD. Using transfections of U-2 OS and HEK293 cells, western blot and immunocytochemistry data demonstrate that RNF207 and the HERG (human ether-a-go-go-related gene) potassium channel interact and co-localize. Furthermore, RNF207 overexpression significantly elevated total and membrane HERG protein and HERG-encoded current density by approximately 30-50%, which was dependent on the intact N-terminal RING domain of RNF207. Finally, co-expression of RNF207 and HSP70 increased HERG expression as compared to HSP70 alone. This effect was dependent on the C-terminus of RNF207. Taken together, the evidence is strong that RNF207 is an important regulator of action potential duration likely via effects on HERG trafficking and localization in a heat shock protein-dependent manner.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes